Caretaker gene

Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein grouped these cancer susceptibility genes into two classes: 'caretakers' and 'gatekeepers'. In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa, and Martin Nowak; 'landscaper' genes. Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein grouped these cancer susceptibility genes into two classes: 'caretakers' and 'gatekeepers'. In 2004, a third classification of tumor suppressor genes was proposed by Franziska Michor, Yoh Iwasa, and Martin Nowak; 'landscaper' genes. Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes. In contrast to caretaker genes, gatekeeper genes encode gene products that act to prevent growth of potential cancer cells and prevent accumulation of mutations that directly lead to increased cellular proliferation. The third classification of genes, the landscapers, encode products that, when mutated, contribute to the neoplastic growth of cells by fostering a stromal environment conducive to unregulated cell proliferation. The process of DNA replication inherently places cells at risk of acquiring mutations. Thus, caretaker genes are vitally important to cellular health. Rounds of cell replication allow fixation of mutated genes into the genome. Caretaker genes provide genome stability by preventing the accumulation of these mutations. Factors that contribute to genome stabilization include proper cell-cycle checkpoints, DNA repair pathways, and other actions that ensure cell survival following DNA damage. Specific DNA maintenance operations encoded by caretaker genes include nucleotide excision repair, base excision repair, non-homologous end joining recombination pathways, mismatch repair pathways, and telomere metabolism. Loss of function mutations in caretaker genes allow mutations in other genes to survive that can result in increased conversion of a normal cell to a neoplastic cell, a cell that; (1) divides more often than it should or (2) does not die when conditions warrant cell death. Thus, caretaker genes do not directly regulate cell proliferation. Instead, they prevent other mutations from surviving for example by slowing the cell division process to enable DNA repair to complete, or by initiating apoptosis of the cell. In genetic knock-out and rescue experiments, restoration of a caretaker gene from the mutated form to the wildtype version does not limit tumorigenesis. This is because caretaker genes only indirectly contribute to the pathway to cancer. Inactivation of caretaker genes is environmentally equivalent to exposing the cell to mutagens incessantly. For example, a mutation in a caretaker gene coding for a DNA repair pathway that leads to the inability to properly repair DNA damage could allow uncontrolled cell growth. This is the result of mutations of other genes that accumulate unchecked as a result of faulty gene products encoded by the caretakers. In addition to providing genomic stability, caretakers also provide chromosomal stability. Chromosomal instability resulting from dysfunctional caretaker genes is the most common form of genetic instability that leads to cancer in humans. In fact, it has been proposed that these caretaker genes are responsible for many hereditary predispositions to cancers.